Claims for Patent: 5,013,556

Summary for Patent: 5,013,556

Title:

Liposomes with enhanced circulation time

Abstract:

A liposome composition which contains between 1-20 mole percent of an amphipathic lipid derivatized with a polyalkylether, as exemplified by phosphatidylethanolamine derivatized with polyethyleneglycol. The derivatized lipid enchances the circulation time of the liposomes severalfold, and this enhancement is achieved with either fluid or membrane-rigidifying liposome components. Also disclosed are methods for delivering a drug for slow release from the bloodstream, and for targeting a selected tissue or cells with liposomes, via the bloodstream.

1. A liposome composition for use in delivering a compound via the bloodstream comprising

liposomes composed of vesicle-forming lipids and between 1-20 mole percent of an amphipathic, vesicle-forming lipid derivatized with a polyethyleneglycol, and containing the compound in liposome-entrapped form, and

characterized by a blood level, 24 hours after intravenous injection, which is severalfold times that of the liposomes in the absence of the derivatized lipid.

2. The composition of claim 1, wherein the liposomes have a selected average size in the size range between about 0.05 and 0.5 microns.

3. The composition of claim 2, wherein the polyethyleneglycol has a molecular weight is between about 1,000 to 5,000 daltons.

4. The composition of claim 2, wherein the amphipathic lipid is a phospholipid having a polar head group at which the polyethyleneglycol is derivatized, and the liposomes are characterized by a blood circulation lifetime, as measured by the
percent liposome marker retained in the blood 24 hours after intravenous injection of the liposomes, which is greater than about 5 percent of the total amount administered.

5. The composition of claim 4, wherein the amphipathic lipid is a phospholipid and the liposomes are characterized by a blood circulation lifetime, as measured by the percent liposome marker retained in the blood 24 hours after intravenous
injection of the liposomes, which is greater than about 10 percent of the total amount administered.

6. The composition of claim 4, wherein the phospholipid is phosphatidylethanolamine, and the polyethyleneglycol is coupled to the phospholipid through a lipid amine group.

7. The composition of claim 5, wherein the phospholipid contains acyl chains which are predominantly 18-carbon acyl chains with at least one unsaturated bond.

8. The composition of claim 7, wherein the phospholipid is a phosphatidylethanolamine, and the polyethyleneglycol is coupled to the phospholipid through a lipid amine group.

10. The composition of claim 1, which is characterized by a blood/RES ratio, 24 hours after intravenous administration, which is at least about tenfold greater than that of the same liposomes in the absence of the derivatized amphipathic lipid.

11. The composition of claim 10, wherein the vesicle-forming lipids making up the liposomes are selected to produce a selected rate of release of the drug from the liposomes circulating in the bloodstream.

12. The composition of claim 11, for the treatment of malignancy, wherein the drug is an amphipathic anti-tumor compound.

13. The composition of claim 12, wherein the drug is doxorubicin or a pharmacologically acceptable analog or salt thereof.

14. The composition of claim 1, wherein the polyalkylether is linked to the amphipathic lipid through an esterase-or peptidase-sensitive linkage.

15. The composition of claim 1, wherein the liposomes include a surface-bound ligand which is effective to bind specifically and with high affinity to ligand-binding molecules carried on the surface of specific cells circulating in the
bloodstream.

16. The composition of claim 15, wherein the surface-bound ligand is an antibody effective to bind specifically and with high affinity to an antigen which is expressed in a cell in the bloodstream in a disease state.

17. The composition of claim 15, wherein the surface-bound ligand is CD4 peptide which is effective to bind to HIV-infected T cell or B cells.

18. A method of producing a severalfold increase in the blood-circulation time of intravenously administered liposomes formed of vesicle-forming lipids and containing an entrapped compound, as measured by the percent liposome marker retained in
the blood 24 hours after intravenous injection, substantially independent of the degree of saturation of said vesicle-forming lipids, comprising

forming the liposomes to include between about 1-20 mole percent an amphipathic, vesicle-forming lipid derivatized with a polyethyleneglycol.

19. A method of enhancing the uptake, by the reticuloendothelial system, of cells carrying surface-specific ligand-binding molecules which are characteristic of a disease state, comprising

preparing a suspension of liposomes containing between 1-20 mole percent of an vesicle-forming lipid derivatized with a polyethyleneglycol, and a surface-bound ligand effective to bind specifically and with high affinity to said ligand-binding
molecule, and

administering said suspension intravenously.

20. The method of claim 19, wherein the liposomes have a selected average size in the size range between about 0.05 and 0.5 microns.

21. The method of claim 19, for increasing the blood-circulation time of intravenously administered liposomes, as measured by the percent liposome marker retained in the blood 24 hours after intravenous injection of the liposomes, to a level
which is greater than about 10 percent of the total amount of lipid administered, wherein the amphipathic lipid is a phospholipid, and the polyethyleneglycol has a molecular weight between about 1,000 to 5,000 daltons.

22. The method of claim 19, wherein adding is effective to enhance the blood circulation lifetime 24 hours after intravenous administration, by at least about tenfold over that observed with the same liposomes in the absence of the derivatized
amphipathic lipid.

23. A method of administering a compound intravenously, to achieve a level of compound in the bloodstream, 24 hours after drug administration, which is at least about 5 percent of the total amount of compound administered, comprising

preparing a suspension of liposomes composed of vesicle-forming lipids and between 1-20 mole percent of an amphipathic, vesicle-forming lipid derivatized with a polyethyleneglycol, and the compound, in liposome-entrapped form, and

intravenously administering an amount of the suspension containing a pharmacologically acceptable amount of the drug.

24. The method of claim 23, wherein the polyethyleneglycol has a molecular weight of between about 1,000 and 5,000 daltons.

25. The method of claim 23, wherein the vesicle-forming lipid is a phospholipid, and the level of compound in the bloodstream, 24 hours after liposome administration, is at least about 10 percent of the total compound administered.

preparing a suspension of liposomes containing between 1-20 mole percent of an vesicle-forming lipid derivatized with a polyethyleneglycol, a surface-bound ligand effective to bind specifically and with high affinity to said ligand-binding
molecule, and the drug, in liposome-entrapped form, and

intravenously administering an amount of the suspension containing a pharmacologically acceptable amount of the drug.

27. The method of claim 26, wherein the polyethyleneglycol has a molecular weight of between about 1,000 and 5,000 daltons.

28. The method of claim 27, wherein the vesicle-forming lipid is a phospholipid.

29. The method of claim 26, wherein the target tissue is a solid tumor carrying a tumor specific antigen, and the ligand is an antibody specific against such antigen.

30. The method of claim 26, wherein the target tissue is a solid tumor, and the drug is doxorubicin or a pharmacologically acceptable analog or salt thereof.

31. The method of claim 19, wherein the polyethyleneglycol has a molecular weight of between about 1,000 and 5,000 daltons.

32. The method of claim 19, wherein the vesicle-forming lipid is a phospholipid.

33. The method of claim 19, wherein the cells are HIV-infected T-cells or B cells and the surface-bound D4 peptide.

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